It is often the case that poorly water soluble pharmacological compounds are difficult to administer to living organisms in an effective manner because of one or more problems including poor bioavailability, too rapid decomposition and excretion, which creates a need for frequent re-dosing, and irritation or tissue damage at the location of introduction.
The boavailability of poorly water soluble, orally administered drug is a major challenge for the pharmaceutical industry as many newly launched drugs possess low aqueous solubility, which leads to poor dissolution and low absorption. Furthermore, poor solubility results in variability in absorption and lack of dose proportionality. Compounding the problems of poor absorption is the problem that pharmacologically useful compounds may be substantially degraded in the gastrointestinal tract before absorption can occur. Solutions have been proposed including Self-Emulsifying Drug Delivery Systems (SEDDS's), defined as isotropic mixtures of one or more hydrophilic solvents and co-solvents/surfactants that are capable to form fine oil-in-water (o/w) emulsions upon mild agitation and dilution in gastrointestinal fluids, and various types of emulsions or suspensions.
A further problem of oral drug administration is the potential for harm to the gastrointestinal tract. This problem is most commonly associated with non-steroidal anti-inflammatory drugs (NSAID's). NSAID's diminish the production of prostaglandins by inhibiting cyclooxygenase enzymes, either COX-1 or COX-2 or both. NSAID's that inhibit COX-1 enzymes interfere with prostaglandin production and blood clotting in the gastrointestinal tract and oral ingestion may lead to gastrointestinal distress and ulceration. For this reason, COX-2 inhibitors have been sought as oral medications. However, COX-2 inhibiting drugs are also associated with increased risk of heart attack and stroke and currently celecoxib is the only COX-2 NSAID available in the United States, and it is available only by prescription. Topical administration is a potential solution for COX-1 inhibiting NSAID's including aspirin (ortho-acetyl salicylic acid), ibuprofen (p-isobutyl 2-propenoic acid), and naproxen ((+)-(S)-2-(6-methoxynaphthalen-2-yl) propanoic acid), which are considered much safer than COX-2 inhibitors and have long been available as over the counter products. Unfortunately, in the United States the only products of these medications are oral forms, and topical products available elsewhere are characterized by poor bioavailability. While it is very desirable to provide COX-1 Inhibiting NSAID compounds as topical medications, the only topical NSAID products available in the United States contain diclofenac as the sodium salt dissolved in solvent systems based on propylene glycol, alcohols and dimethylsulfoxide, and are known to cause irritation in significant proportions of patients.
Whether for oral, rectal, intraperitoneal or topical administration, there is a need to improve the usefulness of poorly water soluble high Kow pharmacologically active compounds including NSAID's by improving bioavailability of drug delivery via transmucosal and transdermal routes. For parenteral administration, there is a need to provide effective dispersed forms of poorly water soluble high Kow drugs.
It would be desirable to have liposomal forms of high Kow compounds including NSAID's that are safe, offer high bioavailability, have pharmacologically meaningful concentrations of active compounds, have acceptable organoleptic properties and cosmetically desirable feel, and which are available from simple and reliable manufacturing processes.
A problem with nanoparticle carriers for high pKow, water insoluble drugs is failure to effectively encapsulate the drug in the nanoparticle, resulting in formation of crystals of drug in the product. Crystallization of active pharmaceutical ingredients is unacceptable because a portion of the drug is in a form with lower bioavailability, resulting in diminished efficacy and lack of dose proportionality. Heretofore there are no known nanoparticles which effectively encapsulate ibuprofen as the neutral high pKow, water insoluble compound.